This invention relates to prostaglandin E2 agonist or antagonist such as oxazole compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
Some oxazole compounds are known, for example, in WO 95/17393, WO 95/24393 and WO 97/03973.
This invention relates to oxazole compounds. More particularly, this invention relates to oxazole compounds and pharmaceutically acceptable salts thereof which are useful as prostaglandin E2 (hereinafter described as PGE2) agonist or antagonists.
Accordingly, one object of this invention is to provide new and useful oxazole compounds and pharmaceutically acceptable salts thereof.
Another object of this invention is to provide processes for preparing of the oxazole compounds or pharmaceutically acceptable salts thereof.
A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, said oxazole compounds or pharmaceutically acceptable salts thereof.
A still further object of this invention is to provide use of the oxazole compounds and pharmaceutically acceptable salts thereof for the manufacture of medicaments for treating or preventing PGE2 mediated diseases.
A still more further object of this invention is to provide use of prostaglandin E2 antagonist (especially, EP4 receptor blocker) such as oxazole compounds and pharmaceutically acceptable salts thereof for the manufacture of medicaments for treating or preventing mesangial proliferative glomerulonephritis.
The oxazole compounds of this invention can be represented by the following formula (I): 
wherein
R1 is aryl which may be substituted with halogen(s),
R2 is aryl which may be substituted with halogen(s),
X is single bond 
xe2x80x83or SO2,
R3 and R4 are independently hydrogen or suitable substituent,
(wherein X is 
xe2x80x83neither R3 nor R4 is hydrogen),
R3 and R4 may be linked together to form 
xe2x80x83is N-containing heterocyclic group which may be substituted with one or more suitable substituent(s),
R5 is
(1) hydrogen,
(2) hydroxy,
(3) carboxy, or
(4) protected carboxy,
A1 is lower alkylene or single bond, 
xe2x80x83is cyclo(C3-C9)alkane or cyclo(C5-C9)alkene,
or a pro-drug thereof, or a pharmaceutically acceptable salt thereof.
The compounds of formula (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers. Furthermore certain compounds of formula (I) which contain alkenyl groups may exist as cis- or trans-isomers. In each instance, the invention includes both mixtures and separate individual isomers.
The compounds of the formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
The compound of the formula (I) and a salt thereof can be in a form of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate.
Also included in the scope of invention are radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies, and any form of the crystal of the compound (I).
According to the present invention, the oxazole compounds (I) or a pharmaceutically acceptable salt thereof can be prepared by the following Processes 1 to 5. 
wherein
R1 is aryl which may be substituted with halogen(s),
R2 is aryl which may be substituted with halogen(s),
X is single bond
xe2x80x83or SO2,
R3 and R4 are independently hydrogen or suitable substituent,
(wherein X is
xe2x80x83neither R3 nor R4 is hydrogen),
R3 and R4 may be linked together to form
xe2x80x83is N-containing heterocyclic group which may be substituted with one or more suitable substituent(s),
R4a is acyl which may be substituted with aryl,
R5 is
(1) hydrogen,
(2) hydroxy,
(3) carboxy, or
(4) protected carboxy,
R6 is acyl or hydroxy,
R7 is lower alkyl, ar(lower)alkyl or aryl,
A1 is lower alkylene or single bond,
xe2x80x83is cyclo(C3-C9)alkane or cyclo(C5-C9)alkene,
The starting compounds (II) or a salt thereof can be prepared according to a similar method described in WO 95/17393, below-mentioned Preparations, and the like.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are explained in detail as follows.
Suitable xe2x80x9carylxe2x80x9d and aryl moiety in the terms xe2x80x9car(lower)alkylxe2x80x9d, xe2x80x9caryloxyxe2x80x9d, xe2x80x9car(lower)alkenylxe2x80x9d, xe2x80x9carylsulfonylxe2x80x9d, xe2x80x9car(lower)arylsulfonylxe2x80x9d, xe2x80x9car(lower)alkylsulfonylxe2x80x9d, and xe2x80x9caryl oxysulfonylxe2x80x9d may include phenyl, lower alkylphenyl (e.g., tolyl, ethylphenyl, propylphenyl, etc.), naphthyl or the like.
Suitable xe2x80x9chalogenxe2x80x9d may include fluorine, chlorine, bromine, or iodine.
The term xe2x80x9clowerxe2x80x9d is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated.
Suitable xe2x80x9clower alkylxe2x80x9d and lower alkyl moiety in the terms xe2x80x9clower alkylaminoxe2x80x9d, xe2x80x9car(lower)alkylxe2x80x9d, xe2x80x9ccarboxy(lower)alkylxe2x80x9d, xe2x80x9chydroxy(lower)alkylxe2x80x9d, xe2x80x9car(lower)alkylsulfonylxe2x80x9d, and lower alkylsulfonyl may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl or the like, preferably one having 1 to 4 carbon atom(s).
Suitable xe2x80x9clower alkylaminoxe2x80x9d may include mono- or di-(lower)alkylamino, such as methylamino, dimethylamino, ethylamino, diethylamino, or the like.
Suitable xe2x80x9clower alkoxyxe2x80x9d and lower alkoxy moiety in the term xe2x80x9chydroxy(lower)alkoxyxe2x80x9d may include methoxy, ethoxy propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy, or the like, preferably methoxy.
Suitable xe2x80x9cheterocyclic groupxe2x80x9d may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one nitrogen atom. And especially preferable heterocyclic ring containing nitrogen may be ones such as
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidinyl, pyrazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g., 1H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.,;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azacycloheptyl, azacyclooctyl, perhydroazepinyl, etc.,;
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atom(s), for example, indolyl, 2,3-dihydroindolyl, isoindolyl, indolinyl, indazolyl, isoindolinyl, indolizinyl, benzimidazolyl, quinolyl, 1,2,3,4-tetrahydroquinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl,etc.,), dihydrotriazolopyridazinyl, etc.,;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, dihydroisoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 2,5-oxadiazolyl, etc.,), etc.,
saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholino, etc.,;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.,;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, thiepinyl, etc.,;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl), etc.,;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.,;
unsaturated condensed heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc., and the like.
Suitable acyl and acyl moiety in the terms of xe2x80x9cacylaminoxe2x80x9d and xe2x80x9cacyloxyxe2x80x9d may include aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring.
And, suitable examples of the said acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkenoyl (e.g., propionyl, 2-methylpropionyl, butenoyl, or the like, preferably one having 3 to 4 carbon atom(s)); aroyl (benzoyl, naphthoyl, etc.); lower alkoxyaroyl (methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, isopropoxyphenylcabonyl, methoxynaphthylcarbonyl, ethoxynaphthylcarbonyl, propoxynaphtylcarbonyl, isopropoxynaphthyl-carbonyl, etc.); heterocyclic carbonyl (xe2x80x9cheterocyclic moietyxe2x80x9d in the term xe2x80x9cheterocyclic carbonylxe2x80x9d can be referred above); bridged cyclic(lower)alkanecarbonyl (bicyclo[2.2.1]hept-2-yl-carbonyl, bicyclo[3.2.1]oct-2-yl-carbonyl, bicyclo[3.2.2]non-2-yl-carbonyl, bicyclo[3.2.2]non-3-yl-carbonyl, bicyclo[4.3.2]undec-2-yl-carbonyl, bicyclo[4.3.2]undec-3-yl-carbonyl, bicyclo[2.2.2)oct-2-en-2-yl-carbonyl, bicyclo3.2.2]non-3-en-3-yl-carbonyl, tricyclo[5.3.1.1]dodec-2-yl-carbonyl, tricyclo[5.3.1.1]dodec-3-yl-carbonyl, adamantylcarbonyl, etc.); cyclo(lower)-alkanecarbonyl (cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), carbamoyl which may be substituted with mono- or di-(lower)alkyl (e.g. dimethylcarbamoyl, etc.) and the like.
Suitable xe2x80x9ccyclo(lower)alkylxe2x80x9d may include cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, or the like.
Suitable xe2x80x9ccyclo(lower)alkenylxe2x80x9d may include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or the like.
Suitable xe2x80x9cprotected carboxyxe2x80x9d may include carboxylate, esterified carboxy, or the like.
Suitable example of the ester moiety of an esterified carboxy may be the ones such as lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.) which may have at least one suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl [e.g., acetoxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, etc.], halo(lower)alkyl (e.g., 2-iodoethyl, 2,2,2-trichloroethyl, etc.); lower alkenyl (e.g., vinyl, allyl, etc.); lower alkynyl (e.g., ethynyl, propynyl, etc.); ar(lower)alkyl which may have at least one suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, etc.); aryl which may have at least one suitable substituent(s) (e.g., phenyl, tolyl, 4-chlorophenyl, tert-butylphenyl, xylyl, mesityl, cumenyl, etc.); phthalidyl; or the like.
Suitable xe2x80x9clower alkylenexe2x80x9d may include straight or branched one having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene, preferably one having 1 to 3 carbon atom(s), more preferably methylene.
Suitable xe2x80x9ccyclo(C3-C9)alkanexe2x80x9d may include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, or the like, preferably one having 5 to 7 carbon atoms.
Suitable xe2x80x9ccyclo(C5-C9)alkenexe2x80x9d may include cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, or the like, preferably one having 5 to 7 carbon atoms.
Preferred embodiments of the oxazole compounds (I) are as follows
wherein
R1 is aryl which may be substituted with halogen(s),
R2 is aryl which may be substituted with halogen(s),
X is single bond,
xe2x80x83or SO2,
R3 and R4 are independently
(1) hydrogen;
(2) hydroxy;
(3) lower alkyl which may be substituted with one or more substituent(s) selected from the group consisting of:
(a) hydroxy,
(b) cyano,
(c) lower alkoxy,
(d) hydroxy(lower)alkoxy,
(e) cyclo(lower)alkyl,
(f) cyclo(lower)alkenyl,
(g) amino,
(h) lower alkylamino,
(i) carbamoyl,
(j) carboxy,
(k) protected carboxy,
(l) heterocyclic group optionally substituted with ar(lower)alkyl or oxo, and
(m) aryl optionally substituted with
hydroxy,
carboxy,
protected carboxy,
carboxy(lower)alkyl, or
lower alkoxy which may be substituted with carboxy or protected carboxy;
(4) lower alkoxy which may be substituted with aryl(s);
(5) aryl which may be substituted with one or more substituent(s) selected from the group consisting of:
(a) aryloxy,
(b) acylamino, and
(c) carbamoyl;
(6) cyclo(lower)alkyl which may be substituted with hydroxy(s);
(7) arylsulfonyl;
(8) ar(lower)alkylsulfonyl;
(9) lower alkylsulfonyl;
(10) aryloxysulfonyl;
(11) heterocyclic group which may be substituted with one or more substituent(s) selected from the group consisting of:
(a) ar(lower)alkyl,
(b) aryl,
(c) protected carboxy,
(d) lower alkyl, and
(e) oxo;
(12) acyl which may be substituted with aryl; or
(13) carbamoyl which may be substituted with acyl, ar(lower)alkyl, or arylsulfonyl,
(wherein X is
xe2x80x83neither R3 nor R4 is hydrogen),
R3 and R4 may be linked together to form
xe2x80x83is N-containing heterocyclic group which may be substituted with one or more substituent(s) selected from the group consisting of:
(1) lower alkyl,
(2) aryl,
(3) protected carboxy,
(4) hydroxy(lower)alkyl,
(5) ar(lower)alkyl,
(6) hydroxy,
(7) oxo, and
(8) lower alkylamino,
R5 is
(1) hydrogen,
(2) hydroxy,
(3) carboxy, or
(4) protected carboxy,
A1 is lower alkylene or single bond,
xe2x80x83is cyclo(C3-C9)alkane or cyclo(C5-C9)alkene,
or a pro-drug thereof, or a pharmaceutically acceptable salt thereof.
More preferred embodiments of the oxazole compounds (I) are as follows:
wherein
R1 is aryl,
R2 is aryl,
X is single bond
xe2x80x83or SO2,
R3and R4 are independently
(1) hydrogen;
(2) hydroxy;
(3) lower alkyl which may be substituted with one or more substituent(s) selected from the group consisting of:
(a) hydroxy,
(b) cyano,
(c) lower alkoxy,
(d) hydroxy(lower)alkoxy,
(e) cyclo(lower)alkyl,
(f) cyclo(lower)alkenyl,
(g) amino,
(h) lower alkylamino,
(i) carbamoyl,
(j) carboxy,
(k) protected carboxy,
(l) heterocyclic group optionally substituted with ar(lower)alkyl or oxo, and
(m) aryl optionally substituted with
hydroxy,
carboxy,
protected carboxy,
carboxy(lower)alkyl, or
lower alkoxy which may be substituted with carboxy or protected carboxy;
(4) lower alkoxy which may be substituted with aryl(s);
(5) aryl which may be substituted with one or more substituent(s) selected from the group consisting of:
(a) aryloxy,
(b) acylamino, and
(c) carbamoyl;
(6) cyclo(lower)alkyl which may be substituted with hydroxy(s);
(7) arylsulfonyl;
(8) ar(lower)alkylsulfonyl;
(9) lower alkylsulfonyl;
(10) aryloxysulfonyl;
(11) heterocyclic group which may be substituted with one or more substituent(s) selected from the group consisting of:
(a) ar(lower)alkyl,
(b) aryl,
(c) protected carboxy,
(d) lower alkyl, and
(e) oxo;
(12) acyl which may be substituted with aryl; or
(13) carbamoyl which may be substituted with acyl, ar(lower)alkyl, or arylsulfonyl,
(wherein X is
xe2x80x83neither R3 nor R4 is hydrogen),
R3 and R4 may be linked together to form
xe2x80x83is N-containing heterocyclic group which may be substituted with one or more substituent(s) selected from the group consisting of:
(1) lower alkyl,
(2) aryl,
(3) protected carboxy,
(4) hydroxy(lower)alkyl,
(5) ar(lower)alkyl,
(6) hydroxy,
(7) oxo, and
(8) lower alkylamino,
R5 is hydrogen,
A1 is lower alkylene,
xe2x80x83is
(1) cyclohexane,
(2) cyclohexene,
(3) cyclopentane, or
(4) cyclopentene,
or a pro-drug thereof, or a pharmaceutically acceptable salt thereof.
Furthermore preferred embodiments of the oxazole compounds (I) are as follows
wherein
R1 is phenyl,
R2 is phenyl,
X is
xe2x80x83or SO2,
R3 and R4 are independently
(1) hydrogen;
(2) lower alkyl which may be substituted with one or more substituent(s) selected from the group consisting of:
(a) hydroxy,
(b) heterocyclic group, and
(c) phenyl;
(3) lower alkoxy which may be substituted with phenyl; or
(4) phenyl which may be substituted with phenyloxy;
(wherein X is
xe2x80x83neither R3 nor R4 is hydrogen),
R3 and R4 are linked together to form
xe2x80x83is N-containing heterocyclic group;
R5 is hydrogen,
A1 is methylene,
xe2x80x83is
(1) cyclohexane,
(2) cyclohexene,
(3) cyclopentane, or
(4) cyclopentene,
or a pro-drug thereof, or a pharmaceutically acceptable salt thereof.
The most preferred embodiment of the oxazole compounds (I) is N-[(2-hydroxy-2-phenyl)ethyl]-3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide, N-(2,2-diphenylethyl)-3-{[(1S,2R)-2-(4,5-diphenyl-oxazol-2-yl)-1-cyclopentyl]methyl}benzamide, N-benzyloxy-3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzamide or N-benzylsulfonyl-3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzamide.
The processes for preparing the object and starting compounds of the present invention are explained in detail in the following.
Process 1
The compound (IV) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof, with the compound (III) or its reactive derivative at the amino group or a salt thereof.
Suitable reactive derivative of the compound (III) may include Schiff""s base type amino or its tautomeric enamine type isomer formed by the reaction of the compound (III) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (III) with a silylating reagent such as N,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide, or the like.
Suitable reactive derivative of the compound (II) may include an acid chloride, an acid anhydride, an activated amide, an activated ester, or the like.
Suitable acid anhydride may be a symmetric anhydride or a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfuric acid, thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, etc.); aromatic carboxylic acid (e.g., benzoic acid, chlorobenzoic acid, fluorobenzoic acid, nitrobenzoic acid, etc.), or the like.
Suitable activated amide may be imidazolylamide, 4-substituted imidazolylamide, dimethylpyrazolylamide, triazolylamide, tetrazolylamide, or the like.
Suitable activated ester may be dimethyliminomethyl [(CH3)2N+xe2x95x90CHxe2x80x94] ester, vinyl ester, propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, methanesulfonylphenyl ester, phenyl thioester, p-nitrophenyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, 8-quinolyl thioester, an activated ester with a N-hydroxy compound (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2H-pyridone, N-hydroxysuccinimido, N-hydroxybenzotrioxazole, N-hydroxyphthalimide, etc.), or the like.
These reactive derivatives can optionally be selected from them according to the kind of compound (II) to be used.
When the compound (II) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of condensing agent.
Suitable condensing agent may include a carbodiimide (e.g., N,Nxe2x80x2-dicyclohexylcarbodiimido, N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl) carbodiimido, N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimido or its hydrochloride) diphenylphosphinic azido, diphenylphosphinic chloride, diethylphosphoryl cyanide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, N,Nxe2x80x2-carbonyldiimidazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, cyanuric chloride, or the like.
The reaction may be also carried out in the presence of organic or inorganic base such as alkali metal carbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, or the like.
The reaction is usually carried out in a conventional solvent such as water, acetone, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
Suitable salts of the object compound (I) including the compounds (IV) and (V), and the compounds (II) and (V) are pharmaceutically acceptable conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc.), an organic acid salt (e.g., acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with an amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.), or the like.
Process 2
The compound (VI) or a salt thereof can be prepared by reacting the compound (V) or a salt thereof, with the compound (III) or its reactive derivative at the amino group or a salt thereof.
This reaction can be referred to that of Examples 6-1 and 6-2.
Process 3
The compound (IX) or a salt thereof can be prepared by reacting the compound (VII) or a salt thereof, with the compound (VIII) or its reactive derivative at the carboxy group or a salt thereof.
Suitable reactive derivative at the carboxy group may include its halide (carbonyl chloride, carbonyl bromide, etc.), its anhydride, its activated ester and the like.
This reaction can be referred to that of Examples 7-1 and 7-2.
Process 4
The compound (XI) or a salt thereof can be prepared by reacting the compound (VII) or a salt thereof, with the compound (X) or a salt thereof.
This reaction can be referred to that of Examples 7-3, 7-4 and 7-5.
Process 5
The compound (XIII) or a salt thereof can be prepared by reacting the compound (VII) or a salt thereof, with the compound (XII) or its reactive derivative at the sulfo group or a salt thereof.
Suitable reactive derivative at the sulfo group may include its halide (sulfonyl chloride, etc.), its anhydride, its activated ester and the like.
This reaction can be referred to that of Example 7-6.
PGE2 is known as one of the metabolites in an arachidonate cascade. And it is also known that it has various activities such as pain inducing activity, inflammatory activity, uterine contractile activity, a promoting effect on digestive peristalsis, an awaking activity, a suppressive effect on gastric acid secretion, hypotensive activity, blood platelet inhibition activity, bone-resorbing activity, angiogenic activity, or the like.
PGE2-sensitive receptors have been sub-divided into four subtypes, EP1, EP2, EP3 and EP4, and these receptors have a wide distribution in various tissues. The effects associated with EP1 receptor are believed to be mediated by mobilization of Ca2 + from intracellular stores. The EP3 receptor is an example of promiscuous receptor that may couple to different second-messenger systems. Further, the effects associated with EP2 and EP4 receptors may be considered as inhibitory, and are in believed to be associated with a stimulation of adenyl cyclase and an increase in levels of intracellular cyclic AMP. Especially, EP4 receptor may be considered to be associated with smooth muscle relaxation, anti-inflammatory or pro-inflammatory activities, lymphocyte differentiation, antiallergic activities, mesangial cell relaxation or proliferation, gastric or enteric mucus secretion, or the like.
The oxazole compounds represented by the formula (I) or its salts thereof possess binding activities to PGE2-sensitive receptors, specifically to EP4 receptor, therefore they possess a PGE2-antagonizing or PGE2-inhibiting activity.
Therefore, the compounds represented by the formula (1) or its salts thereof are useful for preventing or treating a PGE2 mediated diseases, especially a EP4 receptors-mediated diseases, such as inflammatory conditions, various pains, or the like in human beings or animals.
More particularly, PGE2 agonist or antagonist, such as the compounds represented by formula (I) and its salt thereof, are useful for treating or preventing inflammation and pain in joint and muscle (e.g., rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, etc.), inflammatory skin condition (e.g., sunburn, burns, eczema, dermatitis, etc.), inflammatory eye condition (e.g., conjunctivitis, etc.), lung disorder in which inflammation is involved (e.g., asthma, bronchitis, pigeon fancier""s disease, farmer""s lung, etc.), condition of the gastrointestinal tract associated with inflammation (e.g., aphthous ulcer, Chrohn""s disease, atrophic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.), gingivitis, inflammation, pain and tumescence after operation or injury, pyrexia, pain and other conditions associated with inflammation, allergic disease, systemic lupus crythematosus, scleroderma, polymyositis, tendinitis, bursitis, periarteritis nodose, rheumatic fever, Sjgren""s syndrome, Behcet disease, thyroiditis, type I diabetes, diabetic complication (diabetic microangiopathy, diabetic retinopathy, diabetic neohropathy, etc.), nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin""s disease, Alzheimers disease, kidney dysfunction (nephritis, nephritic syndrome, etc.), liver dysfunction (hepatitis, cirrhosis, etc.), gastrointestinal dysfunction (diarrhea, inflammatory bowel disease, etc.) shock, bone disease characterized by abnormal bone metabolism such as osteoporosis (especially, postmenopausal osteoporosis), hypercalcemia, hyperparathyroidism, Paget""s bone diseases, osteolysis, hypercalcemia of malignancy with or without bone metastases, rheumatoid arthritis, periodonritis, osteoarthritis, ostealgia, osteopenia, cancer cachexia, calculosis, lithiasis (especially, urolithiasis), solid carcinoma, or the like in human being or animal.
Furthermore particularly, PGE2 antagonist (especially, EP4 receptor blocker) such as the compounds represented by formula (I) and its salt thereof are useful for treating or preventing mesangial proliferative glomerulonephritis.
Generally, nephritis is classified into two major categories: glomerulonephritis and interstitial nephritis. Among these, glomerulonephritis is additionally sub-classified as follows:
(1) minimal change;
(2) focal segmental glomerulosclerosis;
(3) membranous nephropathy;
(4) endocapillary proliferative glomerulonephritis;
(5) mesangial proliferative glomerulonephritis;
(6) membranoproliferative glomerulonephritis; and
(7) crescentic glomerulonephritis.
The inventors of the present invention found that PGE2 antagonist (especially EP4-receptor blocker) was effective for treating or preventing mesangial proliferative glomerulonephritis among the above-mentioned symptoms. Specifically, it is a new fact found by the inventors of the present invention that PGE2 antagonist is effective for treating or preventing mesangial proliferative glomerulonephritis. The inventors of the present invention have confirmed that one of PGE2 antagonist, namely, the compound of this invention, is effective for treating or preventing mesangial proliferative glomerulonephritis, as evidenced below in Experiment Data.
The compound represented by the formula (I) or its salts thereof are also useful for the preparation of medicament having diuretic activity, which arc useful for the preparation of drugs indicated treating or preventing various edema (e.g. cardiac edema, cerebral edema, etc.), hypertension such as malignant hypertension or the like, premenstrual tension, urinary calculus, oliguria such as the one caused by acute or chronic failure, hyperphosphaturia, or the like.
In order to show the utility of the object compound (I), pharmacological data of the representative compounds thereof are shown in the following.
[I] Test Compound
(1) N-[(2-hydroxy-2-phenyl)ethyl]-3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide Example 1-47
(2) N-(2,2-diphenylethyl)-3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide Example 1-50
(3) N-benzyloxy-3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzamide Example 2-46
(4) N-benzylsulfonyl-3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzamide Example 2-75
[II] Test Method
The membrane fraction was prepared using COS-7 cells transfected prostanoide receptor subtype (human EP4).
The standard assay mixture contained membrane fraction, [3H]-PGE2 in final volume of 0.25 ml was incubated for 1 hour at 30xc2x0 C. The reaction was terminated by that the mixture was rapidly filtered through a glass filter (GF/B). Then the filter was washed by 4ml of ice-cold buffer at two times. The radioactivity associated with the filter was measured by liquid scintillation counting.
In the experiment for competition of specific [3H]-PGE2 was added at a concentration of 10 xcexcM. The following buffer was used in all reactions.
Buffer: 20 mM Mes (pH 6.0), 1 mM EDTA, 10 mM MgCl2 
The inhibition (%) of each compound at a concentration of 10 xcexcM was shown in Table.
[III] Test Result
Female Wistar rats, 6 weeks old were purchased from SLC (Shizuoka, Japan). Glomerulosclerosis model was produced by intravenous injections (i.v.) of the monoclonal antibody (mAb), MRC OX-7 (Dainippon Co. Ltd., Osaka, Japan). The 8 weeks old rats were divided into 4 groups (10 rats/group). Group 1 was injected saline instead of OX-7 as a normal group and treated with vehicle (0.5% methylcellulose solution) only. Group 2 was also treated with the vehicle only after the injection of 1 mg/kg OX-7 as a control group. Group 3 and Group 4 were treated with N-benzylsulfonyl-3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzamide (Example 2-75), as shown in the following Table. The compound was orally given every day from 5 days before to one day after i.v. administration of the antibody. Urine was collected for 24 hours from the rats in metabolic cages 1 day after injection of OX-7 and the amount of protein in each sample was determined by the biuret method using bovine serum albumine as the standard. All the rats were sacrificed 2 days after injection of OX-7. Blood biochemical analysis was carried out. 
The pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form (e.g., tablet, pellet, troche, capsule, suppository, cream, ointment, aerosol, powder, solution, emulsion, suspension etc.), which contains the object compound (1) or a pharmaceutically acceptable salt thereof as an active ingredient, suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
The pharmaceutical composition of this invention can contain various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose, such as excipient (e.g., sucrose, starch, mannit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.), binding agent (e.g., cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyloneglycol, sucrose, starch, etc.), disintegrator (e.g., starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropylstarch, sodium glycol-starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricant (e.g., magnesium stearate, talc, sodium laurylsulfate, etc.), flavoring agent (e.g., citric acid, mentol, glycine, orange powders, etc.), preservative (e.g., sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.), stabilizer (e.g., citric acid, sodium citrate, acetic acid, etc.), suspending agent (e.g., methyl cellulose, polyvinylpyrrolidone, aluminum stearate, etc.), dispersing agent, aqueous diluting agent (e.g., water), base wax (e.g., cacao butter, polyethyleneglycol, white petrolatum, etc.).
The effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 50 mg/kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, weight, conditions of the patient or the administering method.
The patents, patent applications and publications cited herein are incorporated by referance.
Abbreviations used in this application are as follows:
EtOAc: Ethyl acetate
DMF: N,N-Dimethylformamide
MeOH: Methyl alcohol
NMP: N-Methylpyrrolidinone
DMSO: Dimethylsulfoxide
The following Preparations and Examples are given only for the purpose of illustrating the present invention in more detail.
Preparation 1
To a solution of 1-cyclohexene-1-carboxylic acid (100 g) in methylene chloride (800 ml) was added sulfinyl chloride (117 ml) at room temperature. After stirring the mixture for 4 hours, the solvent was evaporated in vacuo. The residue was diluted with methylene chloride (IL) and benzoin (170 g) and triethylamine (166 ml), and dimethylaminopyridine (10 g) were added to the solution at 0xc2x0 C. under N2. After stirring the mixture for 4 hours at room temperature, the solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and water. The organic layer was washed with 1N-hydrochloric acid solution, saturated sodium hydrogencarbonate, and brine, dried over magnesium sulfate, and evaporated in vacuo. The obtained compound and ammonium acetate (200 g) were dissolved in acetic acid (1500 ml) and the mixture was stirred for 4 hours at 100xc2x0 C. After the solvent was removed, the residue was partitioned between EtOAc and water. The organic layer was washed with water, saturated sodium hydrogencarbonate and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give 1-(4,5-diphenyloxazol-2-yl)-1-cyclohexene (171 g).
1H-NMR (CDCl3, xcex4): 1.6-1.9 (4H, m), 2.2-2.4 (2H, m), 2.5-2.7 (2H, m), 6.90 (1H, m), 7.2-7.8 (10H, m)
MS (m/z): 302(M+H)+
Preparation 2
A solution of AD-mix-xcex1 (30 g) in a mixture of t-butanol (600 ml) and water (600 ml) was stirred for 1 hour, and then methanesulfonamide (9.3 g) and 1-(4,5-diphenyloxazol-2-yl)-1-cyclohexene added to the solution at room temperature. After stirring the mixture for 20 hours at the same temperature, sodium sulfite (60 g) was added, and the mixture was stirred for 30 minutes. The mixture was partitioned between EtOAc and water. The organic layer was washed with 1N-hydrochloric acid solution, saturated sodium hydrogencarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1R,2S)-1,2-dihydroxy-1-(4,5-diphenyloxazol-2-yl)cyclohexane (30 g).
IR (neat, cmxe2x88x921): 3400, 3200, 1460
1H-NMR (CDCl3, xcex4): 1.2-1.9 (7H, m), 2.2-2.4 (1H, m), 3.34 (1H, s), 3.70 (1H, br s), 4.1-4.4 (1H, m), 7.2-7.8 (10H, m)
MS (m/z): 365 (M+H)+
Preparation 3
To a solution of (1R,2S)-1,2-dihydroxy-1-(4,5-diphenyloxazol-2-yl)cyclohexane (18 g) in methylene chloride (200 ml) were added orthoacetic acid trimethyl ester (9.7 ml) and p-toluenesulfonic acid (20 mg) at room temperature under N2. After stirring the mixture for 30 minutes, the solvent was evaporated in vacuo. The residue was diluted with methylene chloride (200 ml) and acetyl bromide (5.8 ml) was added to the solution at 0xc2x0 C. under N2. After stirring the mixture for 2 hours at room temperature, the solvent was evaporated in vacuo, the residue was diluted with MeOH (200 ml), and potassium carbonate (12 g) was added to the solution at room temperature. The mixture was stirred for 2 hours at the same temperature and partitioned between EtOAc and water. The organic layer was washed with 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R,2S)-1-(4,5-diphenyloxazol-2-yl)-1,2-epoxycyclohexane (14.1 g).
1H-NMR (CDCl3, xcex4): 1.2-1.8 (4H, m), 1.9-2.2 (2H, m), 2.2-2.4 (1H, m), 2.6-2.8 (1H, m), 3.83 (1H, m), 7.2-7.6 (10H, m)
MS (m/z): 318 (M+H)+
Preparation 4
To a solution of (1R,2S)-1-(4,5-diphenyloxazol-2-yl)-1,2-epoxycyclohexane (20 g) and copper bromide (3.0 g) in tetrahydrofuran (400 ml) was dropwise added a solution of 3-methoxybenzylmagnesium chloride [prepared from 3-methoxybenzylchloride (50 g) and Mg (9.2 g)] in tetrahydrofuran (500 ml) at xe2x88x9278xc2x0 C. under N2. The mixture was stirred for 2 hours at the room temperature and partitioned between EtoAc and water. The organic layer was washed with 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R,2S)-1-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2-(3-methoxybenzyl)cyclohexane (29.2 g).
IR (Nujol, cmxe2x88x921): 3400, 1600
1H-NMR (CDCl3, xcex4): 1.4-2.4 (9H, m), 3.07 (1H, d, J=10 Hz), 3.52 (1H, m), 3.74 (3H, s), 6.7-6.9 (4H, m), 7.15 (1H, t, J=8 Hz), 7.2-7.8 (10H, m)
MS (m/z): 440 (M+H)+
Preparation 5
A mixture of (1R,2S)-1-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2-(3-methoxybenzyl)cyclohexane (28 g) and p-toluene-sulfonic acid (2.5 g) in toluene (300 ml) was stirred for 4 hours under reflux. The solution was washed with water, saturated sodium hydrogencarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (S)-2-(4,5-diphenyloxazol-2-yl)-1-(3-methoxybenzyl)-2-cyclohexene (16 g).
Hu 1H-NMR (CDCl3, xcex4): 1.4-1.9 (4H, m), 2.1-2.4 (2H, m), 2.53 (1H, dd, J=10.2, 12.8 Hz), 3.1-3.3 (1H, m), 3.31 (1H, dd, J=3.2, 12.8 Hz), 3.77 (3H, s), 6.80 (1H, 8 Hz), 6.9-7.0 (3H, m), 7.20 (1H, t, J=8 Hz), 7.2-7.8 (10 H, m)
MS (m/z): 422 (M+H)+
Preparation 6
To a solution of (S)-2-(4,5-diphenyloxazol-2-yl)-1-(3-methoxybenzyl)-2-cyclohexene (8.5 g) in methylene chloride (100 ml) was added boron tribromide (50ml, 1M solution in methylene chloride) at 0xc2x0 C. After stirring the mixture for 2 hours, the solvent was evaporated in vacuo. The residue was diluted with EtOAc, and the mixture was washed with water and brine. The dried solvent was evaporated in vacuo and dissolved in methylene chloride (50 ml). To the solution were added trifluoromethanesulfonic acid anhydride (5.0 ml) and 2,6-lutidine (6.2 ml) at xe2x88x9278xc2x0 C. After stirring the mixture for 2 hours, the solvent was evaporated in vacuo. The residue was diluted with EtOAc, and the mixture was washed with water, saturated sodium hydrogencarbonate and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenyltrifluoromethanesulfonate (9.1 g).
IR (Nujol, cmxe2x88x921): 1600, 1520, 1480
1H-NMR (CDCl3, xcex4) 1.4-2.0 (4H, m), 2.2-2.4 (2H, m), 2.60 (1H, dd, J=10.4, 13.2 Hz), 3.0-3.2 (1H, m), 3.35 (1H, dd, J=4.0, 13.2 Hz), 6.9 (1H, m), 7.1-7.8 (14H, m)
MS (m/z): 540 (M+H)+
Preparation 7
To a solution of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenyl trifluoromethanesulfonate (7 g) in a mixture of MeOH (30 ml) and DMF (40 ml) were added 1,3-bis(diphenylphosphino)propane (1.1 mg), palladium acetate (0.58 mg), and triethylamine (5.4 ml). After stirring the mixture for 5 hours at 80xc2x0 C. under CO atmosphere, the resultant mixture was partitioned between EtoAc and water and the organic layer was washed with 1N-hydrochloric acid, saturated sodium hydrogencarbonate, and brine. The dried solvent was evaporated in vacuo and the obtained solid was washed with ether to afford methyl (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoate (4.2 g).
IR (Nujol, cmxe2x88x921): 1720
1H-NMR (CDCl3, xcex4) 1.4-2.0 (4H, m), 2.1-2.4 (2H, m), 2.62 (1H, dd, J=10.0, 13.0 Hz), 3.16 (1H, m), 3.33 (1H, dd, J=3.0, 13.0 Hz), 3.88 (3H, s), 6.92 (1H, t, J=4.0 Hz), 7.3-7.8 (12H, m), 7.85 (1H, d, J=8 Hz), 8.00 (1H, s)
MS (m/z): 450 (M+H)+
Preparation 8
To a solution of methyl (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoate (0.3 g) in a mixture of ethanol (8 ml) and tetrahydrofuran (5 ml) was added 1N-sodium hydroxide solution (3.5 ml). After stirring the mixture for 24 hours at the same temperature, the solvent was removed. The residue was partitioned between EtOAc and 1N-hydrochloric acid, and the organic layer was washed with brine. The dried solvent was evaporated in vacuo and the obtained solid was washed with a mixture hexane and ether to afford (S)-3-{[2-(4,5-diphenyl-oxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (0.28 g).
IR (Nujol, cmxe2x88x921): 1700
1H-NMR (CDCl3, xcex4): 1.4-1.9 (4H, m), 2.2-2.4 (2H, m), 2.65 (1H, dd, J=10.0, 13.0 Hz), 3.2 (1H, m), 3.35 (1H, dd, J=3.0, 13.0 Hz), 6.93 (1H, t, J=3.8 Hz), 7.2-7.8 (12H, m), 7.93 (1H, d, J=8 Hz), 8.10 (1H, s)
MS (m/z): 436 (M+H)+
Preparation 9
The following compounds described in (1) to (3) were prepared according to a similar manner to those of Preparations 6, 7 and 8.
(1) 3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]-methyl}benzoic acid
IR (Nujol, cmxe2x88x921): 1680
1H-NMR (CDCl3, xcex4): 1.4-2.5 (6H, m), 2.5-3.1 (4H, m), 7.2-7.8 (12H, m), 7.82 (1H, d, J=8 Hz), 7.93 (1H, S)
MS (m/z): 424 (M+H)+
(2) 3-{[(1SR,2RS)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzoic acid
1H-NMR (CDCl3, xcex4) 1.4-2.5 (6H, m), 2.5-3.1 (4H, m), 7.2-7.8 (12H, m), 7.82 (1H, d, J=8 Hz), 7.93 (1H, S)
MS (m/z): 424 (M+H)
(3) 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]-methyl}benzoic acid
1H-NMR (CDCl3, xcex4): 1.4-1.9 (4H, m), 2.2-2.4 (2H, m), 2.65 (1H, dd, J=10.0, 13.0 Hz), 3.2 (1H, m), 3.35 (1H, dd, J=3.0, 13.0 Hz), 6.93 (1H, t, J=3.8 Hz), 7.2-7.8 (12H, m), 7.93 (1H, d, J=8 Hz), 8.10 (1H, s)
MS (m/z): 436 (M+H)+